The invention relates to the treatment of mood disorders.
Opiates have a long history of treating mood disorders. In the classical world, records indicate that opium was used as a treatment for both ‘melancholia’ and ‘mania’ (Weber et al., Int. Clin. Psychopharmacol. 3:255-266 (1988)). It has also been long noted that opiates can have euphorigenic effects. However, as awareness of opiate addiction increased, the use of potentially-addicting opiate treatment for mood disorders fell out of favor. Interest in opiates as treatments for mood disorders has increased again, as a better understanding of opiate receptor subtypes and their individual involvement in mood and addiction developed.
As in many other neurotransmitter systems, the opiate system involves multiple receptor subtypes. Three kinds of opioid receptors have been identified; mu, kappa, and delta. The best-studied of these receptors are the mu receptors, which are preferentially bound by morphine and related compounds. The endogenous ligands for these receptors are endorphins. Mu receptors are concentrated in regions which mediate analgesic pathways. These receptors are also located in regions which are critical for the reinforcing effects of opiates. Kappa opiate receptors (KOR) are also found in areas mediating addiction and reward. In contrast to many opiate-receptor agonists, activation of KOR is not highly addictive, and co-administration may decrease the addictive potential of other substances (Shippenberg et al., Ann N Y Acad Sci. 937:50-73 (2001)). The endogenous ligand for KOR is dynorphin.
As their location would suggest, studies indicate that mood and reward systems are modulated by the opiate systems (see Todtenkopf et al., Psychopharmacology 172:463-470 (2004) and Pickar et al., Biol. Psychiatry 17:1243-1276 (1982)). Changes in cAMP response element binding protein (CREB) appear to mediate mood and affect animal models of reward and depression (Pliakas et al., J. Neurosci. 21:7397-7403 (2001)). Interestingly, CREB modulates the expression of dynorphin, an endogenous ligand of KOR (see Todtenkopf et al., Psychopharmacology 172:463-470 (2004) and Carlezon et al., Science 282:2272-2275 (1988)).
Therapeutic alternatives for bipolar mania include mood stabilizers such as valproic acid, lithium, and carbamezapine. Alternatives also include neuroleptics such as haldol, trilafon, thorazine, zyprexa, risperdal, seroquel, and clozaril. In addition, benzodiazepines and electro-convulsive treatment may be used to treat bipolar mania. Neuroloeptics have been shown to increase the activity of neurons which produce dynorphin (Ma et al, Neuroscience 121:991-998 (2003)).
There is a need for new therapies for the treatment of mood disorders, such as bipolar mania, which provide a more rapid amelioration of manic symptoms. The profile and actions of the kappa opioid system make drugs that target this system particularly promising as a treatment modality, with relatively low risk of addictive properties.